Sex Hormones in Postmenopausal Women in the Diabetes Prevention Program

描述（由申请人提供）：虽然绝经后是一种普遍的衰老经历，并且由卵巢功能的永久性变化定义，但我们仍然不了解绝经后性激素如何影响糖尿病风险。有趣的观察表明，内源性性激素（ESH）可能有助于绝经后妇女的葡萄糖耐受不良。先前的观察性研究受限于单一的ESH测量，干预研究受限于仅检查外源性激素，缺乏显著的葡萄糖变化，缺乏测量潜在的混杂因素，如胰岛素稳态，或仅检查欧洲血统的高加索人。糖尿病预防计划（DPP）是一项大型随机对照试验（n= 3234），强化生活方式干预和二甲双胍预防糖尿病。DPP招募了空腹血糖受损或糖耐量受损的参与者，其中45%为非白人，DPP还获得了人体测量、胰岛素分泌、胰岛素敏感性、空腹和刺激后血糖的多项测量。大约三分之二是女性，一半的女性在基线时已绝经。因此，DPP提供了一个令人信服的机会来检查内源性性激素（ESH）变化对绝经后妇女葡萄糖耐受不良演变的贡献。我们建议对DPP进行辅助研究，即绝经后妇女性激素研究或SHIP研究。使用基线数据收集和随机化2年后储存的血浆，我们建议使用最先进的质谱技术检测未使用外源性激素的DPP女性（n=865）和使用外源性激素的DPP女性（n=144）的ESH（睾酮、雌二醇、性激素结合球蛋白）和促卵泡激素（FSH）。具体目的1是检查糖尿病预防干预是否与ESH变化有关。具体目的2是通过干预组检查ESH水平的变化是否与葡萄糖的变化相关。具体目的3是研究肥胖、胰岛素敏感性和胰岛素分泌的变化是否解释了这些关联。该提案的调查人员和顾问参与了“全国妇女健康研究”，是青年妇女生命阶段转变方面的专家，以及在青年妇女中进行初步研究的DPP pi，这些研究构成了本研究的基础。该团队包括性激素生物学家、流行病学家和糖尿病学家。民进党及其后续研究得到了NIDDK的支持。DPP资源的持续管理通过DPP协调中心进行，SHIP研究将补充正在进行的DPP辅助研究，检查绝经前妇女和男性的雄激素。DPP庞大、特征鲜明、种族/民族多样化的人群和储存的血浆为评估ESH、肥胖、胰岛素稳态和葡萄糖耐受不良之间的关系提供了一个独特的机会。

DESCRIPTION (provided by applicant): Although postmenopause is a universal experience of aging and is defined by permanent changes in ovarian function, we still do not understand how postmenopausal sex hormones affect diabetes risk. Intriguing observations suggest that endogenous sex hormones (ESH) may contribute to glucose intolerance in postmenopausal women. Previous observational studies have been limited by single measures of ESH, and intervention studies are limited by examination of exogenous hormone only, lack of significant glucose changes, lack of measurement of potential confounders such as insulin homeostasis, or examination only in Caucasians of European ancestry. The Diabetes Prevention Program (DPP) was a large randomized controlled trial (n=3,234) of intensive lifestyle intervention and metformin for prevention of diabetes. The DPP enrolled participants with either impaired fasting glucose or impaired glucose tolerance, 45% of whom were non-white, and the DPP also obtained multiple measures of anthropometry, insulin secretion, insulin sensitivity, and fasting and postchallenge glucose. Approximately two-thirds were women, and half of the women were postmenopausal at baseline. Thus, the DPP offers a compelling opportunity to examine the contribution of changes in endogenous sex hormones (ESH) to the evolution of glucose intolerance in postmenopausal women. We propose an ancillary study to the DPP, the Sex Hormones in Postmenopausal Women or SHIP study. Using plasma stored from the baseline data collection and 2 years after randomization, we propose to examine ESH (testosterone, estradiol, sex hormone binding globulin) and follicle stimulating hormone (FSH) in a subset of DPP women without exogenous hormone use (n=865) and DPP women with exogenous hormone use (n=144) using state-of-the art mass spectrometry. Specific Aim 1 is to examine if diabetes prevention interventions are associated with changes in ESH. Specific Aim 2 is to examine if changes in ESH levels are associated with changes in glucose by intervention arm. Specific Aim 3 is to examine whether changes in adiposity, insulin sensitivity, and insulin secretion explain these associations. Investigators and consultants on this proposal are involved in the Study of Women's Health Across the Nation expert in ESH life stage transitions, as well as DPP PIs who have conducted the initial research in ESH that form the basis for this study. The team includes sex hormone biologists, epidemiologists, and diabetologists. The DPP and its follow-up study are supported by the NIDDK. Ongoing management of DPP resources occurs through the DPP Coordinating Center, and the SHIP study will be complementary to ongoing DPP ancillary studies examining androgens in premenopausal women and androgens in men. The DPP's large, well-characterized, racially/ethnically diverse population and stored plasma provide a unique opportunity to assess the relationships among repeated measures of ESH, adiposity, insulin homeostasis, and glucose intolerance. PUBLIC HEALTH RELEVANCE: Postmenopausal women are at high risk for diabetes, and previous studies suggest that endogenous sex hormones (as opposed to hormone replacement therapy) may play a role. However, previous studies have not examined whether changes in sex hormones are associated with changes in glucose tolerance, and whether such changes might be explained by concurrent changes in adiposity and insulin. Previous studies have not examined the influence of diabetes prevention interventions upon sex hormones. To address these gaps, the proposed SHIP ancillary study will leverage the significant data already collected through the DPP. The SHIP study will provide insight into the pathophysiology of glucose intolerance, and the findings will have implications not only for diabetes prevention but also for other diseases that focus on sex hormones as mediators.